CD137 and regulatory T cells as independent prognostic factors of survival in advanced non-oncogene addicted NSCLC patients treated with immunotherapy as first-line.

BACKGROUND

Immune checkpoint inhibitors (ICIs), administered alone or combined with chemotherapy, are the standard of care in advanced non-oncogene addicted Non-Small Cell Lung Cancer (NSCLC). Despite these treatments' success, most long-term survival benefit is restricted to approximately 20% of patients, highlighting the need to identify novel biomarkers to optimize treatment strategies. In several solid tumors, immune soluble factors, the activatory CD137 Tcells, and the immunosuppressive cell subsets Tregs and MDSCs (PMN(Lox1)-MDSC and M-MDSCs) correlated with responses to ICIs and clinical outcomes thus becoming appealing predictive and prognostic factors. This study investigated the role of distinct CD137 Tcell subsets, Tregs, MDSCs, and immune-soluble factors in NSCLC patients as possible biomarkers.

METHODS

The levels of T cells, MDSCs and soluble factors were evaluated in 89 metastatic NSCLC patients who underwent ICIs as first- or second-line treatment. T cell analysis was performed by cytoflurimetry evaluating Tregs and different CD137 Tcell subsets also combined with CD3, CD8, PD1, and Ki67 markers. Circulating cytokines and immune checkpoints were also evaluated by Luminex analysis. All these parameters were correlated with several clinical factors (age, sex, smoking status, PS and TPS), response to therapy, PFS , and OS . The analyses were conducted in the overall population and in patients treated with ICIs as first-line (naïve patients).

RESULTS

In both groups of patients, high levels of circulating CD137 and CD137PD1 T cells (total, CD4 and CD8) and the soluble factor LAG3 positively correlated with response to therapy. In naïve patients, PMN(Lox1)-MDSCs negatively correlated with clinical response, and a high percentage of Tregs was associated with favorable survival. Moreover, the balance between Treg/CD137 Tcells or PMN(Lox1)-MDSC/CD137 Tcells was higher in non-responding patients and was associated with poor survival. CD137 Tcells and Tregs resulted as two positive independent prognostic factors.

CONCLUSION

High levels of CD137, CD137PD1 Tcells and sLAG3 could predict the response to ICIs in NSCLC patients independently by previous therapy. Combining the evaluation of CD137 Tcells and Tregs also as Treg/CD137 T cells ratio it is possible to identify naive patients with longer survival.